PROJECT SUMMARY Despite advances in combination antiretroviral therapy (cART), human immunodeficiency virus (HIV) infection remains a major public health burden. Current therapeutic regimens often achieve complete viral suppression but require lifelong adherence, as the virus quickly rebounds from tissue and cellular reservoirs following treatment interruption. Moreover, chronic inflammation persists in cART-suppressed individuals and contributes to comorbidities even in the absence of detectable viremia. Thus, a major goal in HIV research is focused on approaches that lead to either sustained viral control or elimination of viral reservoirs (either a `functional' or `sterilizing' cure), with the additional objective to develop approaches that reduce the persistent inflammatory process that complicates disease-free remission during cART treatment. Recent work has highlighted the critical role of the gastrointestinal (GI) tract in HIV persistence, with the GI tract comprising the vast majority of viral reservoirs in the body during cART. Importantly, residual systemic inflammation observed in HIV infected, cART suppressed individuals appears driven by increased GI tract permeability. A substantial body of research has shown a critical role for TNF? in perpetuating the pro- inflammatory cycle that occurs with other GI disorders, such as inflammatory bowel disease. Notably, TNF? has been shown to contribute to the pro-inflammatory milieu that is elevated in HIV infected individuals, but the role of TNF? in GI-associated pathology during HIV disease is not well understood. We hypothesize that persistent damage to the GI tract epithelial barrier is a major cause of residual local and systemic inflammation in HIV infected individuals on cART, which plays an important role in viral reservoir persistence within the GI tract, and attenuating GI tract, and systemic, inflammation will lead to restored gut restoration, immune homeostasis and reduced reservoir persistence. TNF? therefore represents an attractive target for mitigating the inflammatory milieu during the chronic phase of HIV infection. Thus, two different approaches to target TNF? will be utilized in a non-human primate model of HIV infection, i) an FDA-approved antibody against TNF? therapy (adalimumab, Humira) and ii) a novel small molecule inhibitor of the downstream kinase, RIPK1. The extent and characteristics of GI tract pathology and the restoration of immune homeostasis (Aim 1) and the quantity, distribution, and characteristics of the viral reservoir within the GI tract (Aim 2) will be evaluated throughout treatment and following the conclusion of the experiments. Discovering a critical role for TNF? in modulating the GI manifestations of HIV would have a significant impact on the direction of future HIV research and treatment. Moreover, use of either a novel inhibitor that is currently in clinical development, or the re-purposing of an FDA-approved drug, as new therapeutic modalities for HIV infection represent a marked innovation in the search for a cure.